Development of effective recombinant or synthetic peptide vaccines against infectious diseases often requires co-administration of potent adjuvants. Several adjuvants have been developed for clinical use and they induce immune responses with comparable efficacies as Complete Freund's Adjuvant. However, adjuvants have been shown to critically influence the qualities of immune responses. Moreover, the immunological effects of adjuvants are animal species dependent; thus making it difficult to rely on animal models for the design of novel adjuvants for humans. The unique influences of adjuvants on the immune system occur despite the fact that adjuvants have pleomorphic effects on a variety of immune cells and such effects often overlap among different classes of adjuvants. Preliminary studies with gene knockout mice suggested that during active immunizations, adjuvant formulations selectively or preferentially utilize different immune pathways for the potentiation of a particular type of immune response to an antigen, thus leading to unique differences in the responses. The long-term goal of this research is to study the in vivo mechanisms of action of adjuvants with respect to immune pathways usages. This should contribute generalizable scientific principles for the rational selection and design of vaccine adjuvants, and to the improvement of adjuvants' potency and efficacy. Using mice deficient in one or more immune mediators and immunizations with a clinically produced malaria vaccine based on the Plasmodium falciparum Merozoite Surface Protein 1, MSP1, the overall Specific Aims are: 1) To study the induction of antibody and T cell responses to the MSP1 vaccine by CFA, Alum, MDP, MPLs, QS21, MF59, and Montanide adjuvants in terms of their requirements for various cytokines, co-stimulatory and accessory molecules for immunopotentiation. 2) To develop general principles to formulate adjuvant mixtures based on individual adjuvant components' similarities or differences in immune mediator usages; and to enhance the potency of adjuvants by supplementation, up-regulation, or stimulation of the required immune mediators. 3) To determine the immunization conditions; i.e., various adjuvants in the presence and/or absence of specific immune mediators, for the induction of protective (parasite inhibitory) antibodies and to determine if non-protective, blocking antibodies are induced under similar conditions.